The oviducts transport the germ cells in two directions: sperm ascend to- Female germ cells develop in the embryonic yolk sac and ward the ampulla and the zygote descends toward the migrate to the genital ridge where they participate in the uterus mildronate 500mg for sale. This requires coordination between smooth muscle development of the ovary (Table 38 buy mildronate 500 mg mastercard. Without germ contraction, ciliary movement, and fluid secretion, all of cells, the ovary does not develop. Oogonia undergo mi- The uterus is situated between the urinary bladder and tosis only during the prenatal period. On each upper side, an oviduct opens into the uter- contain a finite number of oocytes, estimated to be about 1 ine lumen, and on the lower side, the uterus connects to the million. The puberty, only 200,000 oocytes remain; by age 30, only outer part is the myometrium, composed of multiple layers 26,000 remain; and by the time of menopause, the ovaries of smooth muscle. The inner part, lining the lumen of the are essentially devoid of oocytes. The stroma is permeated by spiral arteries and con- sis, to prepare for the production of a haploid ovum), become tains much connective tissue. The epithelial layer is inter- arrested in prophase of the first meiotic division, and remain rupted by uterine glands, which also penetrate the stromal arrested in that phase until they either die or grow into ma- layer and are lined by columnar secretory cells. The primordial follicle provides an environment for the developing fetus, and (Fig. When pregranulosa The cervix (neck) is a narrow muscular canal that con- cells surround the oocyte, a basement membrane develops, nects the vagina and the body (corpus) of the uterus. The cervix has numerous glands with a colum- A Graafian Follicle Is the Final Stage of nar epithelium that produces mucus under the control of Follicle Development estradiol. As more and more estradiol is produced during the follicular phase of the cycle, the cervical mucus changes Folliculogenesis (also called follicular development) is the from a scanty viscous material to a profuse watery and process by which follicles develop and mature (see Fig. Follicles are in one of the following physiological of the spinnbarkeit can be tested by touching it with a piece states: resting, growing, degenerating, or ready to ovulate. The mucus can form a thread During each menstrual cycle, the ovaries produce a group up to 6 cm under the influence of elevated estradiol. If a of growing follicles of which most will fail to grow to ma- drop of the cervical mucus is placed on a slide and allowed turity and will undergo follicular atresia (death) at some to dry, it will form a typical ferning pattern when under the stage of development. It is lined by several layers of epithelium that change Primordial follicles are generally considered the non- histologically during the menstrual cycle. When estradiol growing resting pool of follicles, which gets progressively levels are low, as during the prepubertal or post- depleted throughout life; by the time of menopause, the menopausal periods, the vaginal epithelium is thin and the ovaries are essentially devoid of all follicles. Primordial fol- secretions are scanty, resulting in a dry and infection-sus- licles are located in the ovarian cortex (peripheral regions ceptible area. Estradiol induces proliferation and cornifi- of the ovary) beneath the tunica albuginea. The theca externa remains fibroblastic constant rate throughout fetal, juvenile, prepubertal, and and provides structural support to the developing follicle. Once primary follicles leave the resting pool, Development beyond the primary follicle is go- they are committed to further development or atresia. Most nadotropin-dependent, begins at puberty, and continues in become atretic, and typically only one fully developed fol- a cyclic manner throughout the reproductive years. The conversion from primordial to pri- follicle continues to grow, theca layers expand, and fluid- mary follicles is believed to be independent of pituitary go- filled spaces or antra begin to develop around the granulosa nadotropins. This early antral stage of follicle development is re- resting to a growing pool is unknown; it could be pro- ferred to as the tertiary follicular stage (see Fig. The grammed by the cell genome or influenced by local ovarian critical hormone responsible for progression from the pre- growth regulators. Mitosis of the granulosa The first sign that a primordial follicle is entering the cells is stimulated by FSH. As the number of granulosa cells growth phase is a morphological change of the flattened increases, the production of estrogens, the binding capac- pregranulosa cells into cuboidal granulosa cells. The ity for FSH, the size of the follicle, and the volume of the cuboidal granulosa cells proliferate to form a single contin- follicular fluid all increase significantly. At this stage, a glassy membrane, the zona the follicle and forming a large 2- to 2. Three tachment through which the granulosa cells communicate distinct granulosa cell compartments are evident in the with the oocyte. Granulosa cells surrounding the oocyte are velopment, consisting of one layer of cuboidal granulosa cumulus granulosa cells (collectively called cumulus cells and a basement membrane. Those cells lining the antral cavity are called The follicle continues to grow, mainly through prolifer- antral granulosa cells and those attached to the basement ation of its granulosa cells, so that several layers of granu- membrane are called mural granulosa cells. Mural and losa cells exist in the secondary follicular stage of develop- antral granulosa cells are more steroidogenically active ment (see Fig. The granulosa cells of secondary follicles ters of human follicles at successive stages of development in 672 PART X REPRODUCTIVE PHYSIOLOGY Primordial Basement membrane follicle Oocyte Granulosa cells Primary Basement membrane follicle Granulosa cells Fully grown oocyte Zona pellucida Secondary Basement membrane follicle Granulosa cells Zona pellucida Fully grown oocyte Presumptive theca Theca externa Basement membrane Fully grown oocyte Early tertiary Multiple layers of follicle granulosa cells Zona pellucida Antrum Theca interna Graafian follicle Theca interna Cumulus oophorus Zona pellucida Antrum (follicular fluid) FIGURE 38. Reproductive En- Granulosa cells docrinology, Infertility, and Genetics. There is a 5-fold increase in follicular di- The follicular fluid contains other substances, including ameter and a 25-fold rise in the number of granulosa cells. As inhibin, activin, GnRH-like peptide, growth factors, opioid the follicle matures, the intrafollicular concentration of FSH peptides, oxytocin, and plasminogen activator. Inhibin and does not change much, whereas that of LH increases and activin inhibit and stimulate, respectively, the release of that of PRL declines.

In contrast to these excitatory effects elevating brain histamine levels with metoprine order mildronate 250mg line, an inhibitor of histamine-N-methyltransferase protects rodents against maximal electroshock although the specificity of the effect remains to be established mildronate 250mg low price. Agonists and antagonists at the H3 autoreceptors, which should decrease and increase histamine release, have been shown to augment and reduce slow-wave sleep in rats and cats. There are in fact numerous demonstra- tions of this using tests which require visual±motor coordination such as vigilance tasks and finger tapping. Since the slowing of such function could result from retarding information processing in the visual cortex it is interesting that the latency of com- ponents of the evoked potential, which follows presentation of a changing (reversing) black and white checkerboard pattern, is prolonged significantly in humans by the H1 antagonist diphenhydramine, which enters the brain, but not by terfenedine which does not (Tharion, McMenemy and Rauch 1994). There is also some evidence that histamine may be involved in food and water intake and thermoregulation (see Hough and Green 1983). NEUROSTEROIDS Neurosteroids differ from nearly all the other transmitters and mediators in that they are lipid-soluble and can easily cross the blood±brain barrier. Thus it is necessary to distinguish those steroids that are produced in the brain from those that find their way there from the circulation after being released from the adrenal cortex or gonads. There are many natural and synthetic steroids that have some effect on neuronal function and can be considered neuroactive but few are actually produced in the brain to act on neurons, i. This also applies to tetrahydrodeoxycorticosterone for although it is formed by reduction of deoxycorticosterone within the brain, its synthesis depends on that steroid coming from the blood. The chemical structures and interrelationship of the neurosteroids listed in (b) and (c) above are shown in Fig. PREG and DHEA are known as 3b-hydroxy-D5-steroids and are also found in peripheral glands as intermediaries between cholesterol and active steroids such as PROG and testosterone. It seems that cholesterol may be the starting point of neurosteroid synthesis in the brain. Cytochrome P450scc, the specific hydroxylase needed for cleavage of the cholesterol side-chain to give PREG, has been found widely in white matter and in myelinating oligodendrocytes, but not in neurons. Enzymes are present for the conversion of PREG to PROG and both are reduced in glia and neurons. This does not occur with DHEA and very little is known of either its synthesis or metabolism. Neurosteroids are widely and fairly evenly distributed in the brain with few note- worthy localisations but the concentration of the conjugated forms (sulphated and reduced) of PREG and DHEA can exceed that of the parent compounds. By contrast, although the concentration of progesterone rises some twelvefold in plasma and eight times in hippocampus of animals and humans as they pass from the follicular to luteal phase of the ovarian cycle, it increases by 300 in the cortex, suggesting a considerable variation in the ability of different brain regions to concentrate it. In considering the neurosteroids as possible NTs it should be remembered that neither specific steroid neurons nor an evoked neuronal release of steroids have been demonstrated. There are, however, receptors for them in the CNS and no shortage of actions attributed to them. Given clinically in the therapy of inflammatory conditions, the glucocorticoids are considered to produce euphoria, followed after prolonged or higher dosing by depression and, of course, when we are stressed the corticocosteroids pumped out by the adrenal cortex easily enter the brain and may initiate some of the behavioural response. In women the premenstrual syn- drome (irritability, depression and anxiety) is thought to be associated in some way with progesterone since not only does its concentration rise then fall during that time but in post-menopausal women the use of sequential oestrogen and progestogen hormone replacement therapy (HRT) shows that similar mood changes accompany only the addition of progestogen. More specifically, in women with epilepsy while the incidence of seizures decreases when plasma progesterone is high, it increases during the immediate premenstrual period as progesterone levels fall, rather as with withdrawing 274 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 13. Pregnenolone (PREG) (1) is synthesised from cholesterol and is then either metabolised, reduced to 20a dihydropregnenolone (7) or sulphated (6), or converted by 3b-hydroxysteroid dehydrogenase to progesterone (PROG) (2) or to dehydroepiandrosterone (DHEA) (3). The former (PROG) can then be reduced to allopregnanolone (3a5aThPROG) (4) and DHEA sulphated to dehydroepiandrosterone sulphate (5). The structures of alphaxalone, a steroid anaesthetic and tetrahydrodeoxy- corticosterone, which is formed in the brain from deoxycorticosterone of peripheral origin, are also shown OTHER TRANSMITTERS AND MEDIATORS 275 an antiepileptic drug. Of course, it cannot be assumed that plasma levels are reflected in the brain but in rats stressed by insertion in the Morris water maze, so that they have to swim to a safe platform (see Chapter 18), there is still some increase in the concen- tration of brain PROG and in particular its reduced metabolic (ThPROG), even after adrenalectomy (Purdy et al. The aggressiveness of castrated male mice exposed to lactating females in a cage can also be reduced by DHEA administration. These observations, while implicating steroids in brain function and behaviour, cannot be taken as a reliable indicator of their actual effect on neuronal function. Nevertheless, some neurosteroids produce CNS depression with a rapid inhibition of neuronal excitability and one progesterone derivative, alphaxalone (3a-hydroxy- 5a pregnane-11, 20 dione, see Fig. Intracellular steroid receptors, which alter gene expression, exist for corticosteroids, oestrogens and progesterone in the brain, as in the periphery but they cannot account for the relatively rapid depression of CNS function induced by some steroids. This was explained when Harrison and Simmonds (1984) discovered that alphaxalone (the steroid anaesthetic) potentiated the duration of GABA-induced currents at the GABAA receptor in slices of rat cuneate nucleus just like the barbiturates (Fig. Depolarisations recorded extracellularly from dorsal funiculus fibres and terminals in the rat cuneate brain slice after superfusion for 2 min with muscimol 2. In the presence of alphaxalone (1 mM), responses to GABA and the GABAA agonist muscimol, but not those to glycine, were substantially enhanced. The effect was reversible with responses slowly returning to normal after 3 h. The sulphated metabolite of PREG is similarly active at low (nM) concentrations. These allosteric effects are still seen after maximal barbiturate potentiation and are not affected by benzodiazepine antagonists suggesting a specific and separate modulating site for the steroids (see Paul and Purdy 1992) although it has not been found. Also while their activity changes with the subunit composition of recombinent GABAA receptors no specific configuration has been established for their effectiveness but expression of a2 with a1  B1 or a2  B1 gives a more responsive receptor than the inclusion of a3 (Shingai, Sutherland and Barnard 1991). The GABA potentiation seen with low concentrations of PREG sulphate changes to antagonism at higher strengths and both this compound and sulphated DHEA, which also inhibits GABAA receptors, are proconvulsant. There is also evidence that the sulphates of PREG and DHEA potentiate NMDA receptors while glucocorticoids reduce seizure threshold without affecting GABA receptors. Thus even without considering reports of effects on glycine sigma and ACh nicotinic receptors, the electrophysiology of the steroids is complex. In practice, although steriods modulate GABAA receptors at realistic nM concentrations, unphysiological mM amounts are required at other ligand-gated ion channels (see Rupprecht and Holsboer 1999).